Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Cancer Immunol Res. 2019 Feb;7(2):183-192. doi: 10.1158/2326-6066.CIR-18-0428. Epub 2019 Jan 16.
Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the "inhibitor of apoptosis proteins" with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell-derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell-derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.
嵌合抗原受体 (CAR) T 细胞疗法已被证明在治疗血液系统恶性肿瘤方面非常成功，特别是急性淋巴细胞白血病和 B 细胞淋巴瘤。然而，CAR T 细胞对实体瘤的疗效不佳，可能是由于肿瘤相关的免疫抑制。在这里，我们证明了用临床 SMAC 模拟物 birinapant 拮抗“凋亡抑制蛋白”，以 TNF 依赖性方式显著增强了 CAR T 细胞的抗肿瘤活性。增强的肿瘤细胞死亡不依赖于穿孔素介导的颗粒外排途径，强调了 CAR T 细胞衍生的 TNF 的细胞毒性潜力。CAR T 细胞疗法与 birinapant 联合使用可显著减少已建立的肿瘤生长，而单独使用任何一种疗法效果相对较差。使用源自患者活检的肿瘤类器官，我们证明了 CAR T 细胞疗法与 SMAC 模拟物联合使用的协同潜力。总之，我们确定了 CAR T 细胞衍生的 TNF 作为一种有效的抗肿瘤效应物，可以通过 SMAC 模拟物进一步利用。
